Crystalline forms of dimethoxy docetaxel and methods for preparing the same

ABSTRACT

The invention relates to anhydrides, solvates and ethanol hetero-solvates and hydrates of dimethoxy docetaxel or (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11-ene-13α-yle, and to the preparation thereof

This application is a divisional of U.S. patent application Ser. No.14/453,087, filed Aug. 6, 2014, which is a divisional of U.S. patentapplication Ser. No. 13/767,966, filed Feb. 15, 2013, now U.S. Pat. No.8,846,959, which is a divisional application of U.S. patent applicationSer. No. 12/837,559, filed Jul. 16, 2010, now U.S. Pat. No. 8,378,128,which is a continuation of International Patent ApplicationPCT/FR2009/000042 filed Jan. 15, 2009, all of which are incorporatedherein by reference; and which claim priority to French PatentApplication No. 0800243 filed on Jan. 17, 2008.

The present invention relates to crystalline forms of dimethoxydocetaxel or 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and tomethods for the preparation thereof.

BACKGROUND OF THE INVENTION

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13 α-yl (2R,3S)-3-tert-butoxy carb onylamino-2-hydroxy-3-phenylpropionate exhibits notable anticancer andantileukaemic properties.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13 α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate isprepared according to the method which is described more particularly inPCT International Application WO96/30355 or PCT InternationalApplication WO99/25704. According to the method described in theseapplications, the product is not crystallized and is not characterized.

It was found that the acetone solvate of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (calledform A) was completely determined and characterized according to thepatent published under number WO2005/028462.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to new crystalline forms, with theexclusion of the acetonate form, the only one known to date.

According to the present invention, it has now been found that certainanhydrous forms, certain ethanolic solvates or heterosolvates andhydrated forms have been completely characterized from a physical andchemical structure point of view.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a Differential Scanning calorimetry (DSC) analysis foranhydrous form D.

FIG. 2 depicts a Powder X-Ray Diffraction (PXRD) analysis for anhydrousform D.

FIG. 3 depicts Fourier Transform InfraRed (FTIR) spectrometry analysisfor anhydrous form D.

FIG. 4 depicts a Powder X-Ray Diffraction (PXRD) analysis for ethanolateform D.

FIG. 5 depicts a Powder X-Ray Diffraction (PXRD) analysis for ethanolateform E.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, among the anhydrous forms of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,five different forms have been identified, among the ethanolic solvatesor heterosolvates of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,four different forms have been identified and among the hydrates of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, twodifferent forms have been identified.

The five anhydrous forms identified were obtained according to thefollowing methods:

The anhydrous form B by a method which consists in heating the acetoneform or form A obtained according to the patent mentioned above, between100 and 110° C. under vacuum or nitrogen sweeping. This treatment ispreferably carried out for at least 9 hours before a return to ambienttemperature without inducing chemical decomposition. Its melting pointby DSC is approximately 150° C. The PXRD diagram of the anhydrous form Bexhibits characteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1,12.7, 13.1, 14.3, 15.4 and 15.9±0.2 degrees 2-theta.

The anhydrous form C is obtained by maturation of the acetone solvateform A, or of the anhydrous form B, in water followed by drying at up to50° C. and maintaining between 0 and 5% RH at ambient temperature. Itsmelting point by DSC is approximately 146° C. The PXRD diagram of theanhydrous form C exhibits characteristic lines located at 4.3, 6.8, 7.4,8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1±0.2 degrees 2-theta. It is,among the various anhydrous forms, the least stable of all the formsdescribed in the present invention. In the presence of a relativehumidity of greater than 5%, it changes to a hydrated form.

The anhydrous form D is obtained according to a first method bycrystallization of the form A in an oil (especially Miglyol), followingby rinsing with an alkane, for example heptane; the second preparationmethod consists in leaving a solution of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in amixture of Polysorbate 80, pH 3.5, ethanol and water (preferably a25/25/50 mixture) to crystallize for approximately 48 hours. Its boilingpoint by DSC is approximately 175° C. (cf. FIG. 1) and is found to bethe highest of all the anhydrous forms isolated. The PXRD diagram of theanhydrous form D (cf. FIG. 2) exhibits characteristic lines located at3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3±0.2 degrees2-theta. The FTIR spectrum of the anhydrous form D exhibitscharacteristic bands located at 979, 1072, 1096, 1249, 1488, 1716, 1747,3436±1 cm⁻¹(cf. FIG. 3). Among all the forms described in the presentinvention, it is the most stable anhydrous form.

The anhydrous form E is obtained at ambient temperature by maturation ofthe acetone form or form A in ethanol so as to intermediately form anethanolic form which is subsequently desolvated under nitrogen sweepingor by heating at approximately 100° C. for 2 hours. Its melting point byDSC is approximately 157° C. The PXRD diagram of the anhydrous form Eexhibits characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8,12.5, 12.7, 13.2, 13.4 and 13.9±0.2 degrees 2-theta.

The anhydrous form F is obtained by desolvating the ethanol/waterheterosolvate at 120° C. under a nitrogen atmosphere for 24 hours andthen maintaining in a dry environment at 0% RH at ambient temperature.Its melting point by DSC is approximately 148° C. The PXRD diagram ofthe anhydrous form F exhibits characteristic lines located at 4.4, 7.2,8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3±0.2 degrees 2-theta.

There are four crystalline forms identified in ethanolic solvate orheterosolvate form:

The ethanolate form B is obtained at ambient temperature by maintainingthe anhydrous form B in an ethanol-vapour-saturated environment. ThePXRD diagram of the ethanolate form B exhibits characteristic lineslocated at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and15.1±0.2 degrees 2-theta.

The ethanolate form D is obtained at ambient temperature by maintainingthe anhydrous form D in an ethanol-vapour-saturated environment. ThePXRD diagram of the ethanolate form D (cf. FIG. 4) exhibitscharacteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5,11.1, 11.5 and 11.9±0.2 degrees 2-theta.

The ethanolate form E is obtained at ambient temperature by maturationof the acetonate form A in ethanol. The PXRD diagram of the ethanolateform E (cf. FIG. 5) exhibits characteristic lines located at 7.1, 8.1,8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2±0.2 degrees 2-theta.

The ethanol/water heterosolvate form F is obtained by maintaining theform B in a minimum amount of ethanol at reflux, slow cooling andisolation at ambient temperature and ambient relative humidity. The PXRDdiagram of the ethanol/water heterosolvate form F exhibitscharacteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3,10.9, 11.2 and 12.2±0.2 degrees 2-theta.

There are two crystalline forms identified in hydrate form:

The monohydrated forms C are obtained at ambient temperature bymaintaining the anhydrous form C in an atmosphere containing at least10% relative humidity. The PXRD diagram of the monohydrate form Cexhibits characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1,11.9, 12.2, 12.6 and 13.3±0.2 degrees 2-theta.

The dihydrate form C is obtained at ambient temperature by maintainingthe anhydrous form C in an atmosphere containing at least 60% relativehumidity. The PXRD diagram of the dihydrate form C exhibitscharacteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7,12.3, 12.6 and 13.2±0.2 degrees 2-theta.

Other, nonethanolic, solvates of the form B were prepared, such as inparticular those obtained with the following solvents: dichloromethane,diisopropyl ether, n-propanol, isopropanol, toluene, methyl isobutylketone, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.

The present invention will be described more fully by means of thefollowing examples which should not be considered to limit theinvention.

Experimental analysis conditions:Differential Scanning calorimetry (DSC):

The measurements were carried out on a T.A. Instruments DSC2010 thermalanalyser. The sample is subjected to temperature programming from 25° C.to 225° C. with a heating rate of 5° C/min. The product is placed in acrimped aluminium capsule and the amount of product analysed is between2 and 5 mg. Constant nitrogen sweeping at 55 mL/min is used in the ovenchamber.

Powder X-Ray Diffraction (PXRD):

The analyses were carried out on a Panalytical X′Pert Pro diffractometerwith a reflection-mode Bragg-Brentano focusing geometry (θ-2θ) assembly.The product analysed is deposited as a thin layer on a silicon singlecrystal. A copper anticathode tube (45 kV/40 mA) supplies an incidentradiation Cu Kα₁ (λ1.5406 Å). The beam is collimated using Sollers slitswhich improve the parallelism and variable slits which limit scattering.An X′Celerator detector completes the device. The diagram recordingcharacteristics are the following: sweeping from 2 to 30 degrees 2θ,counting time from 100 to 500 seconds per step with a step of 0.017°.

Fourier Transform InfraRed (FTIR) spectrometry:

The solid samples were analysed using a Nicolet Nexus spectrometer. Theanalysis is carried out by attenuated total reflectance (ATR) using aSmart Orbit accessory from the company Thermo (single reflection diamondcrystal ATR accessory). The spectral range swept is between 4000 and 400cm⁻¹ with a resolution of 2 cm⁻¹ and an accumulated scan number of 20.

EXAMPLE 1

Two tests of dissolution of approximately 550 mg of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 14 gof Miglyol 812 Neutral oil, Sasol are carried out. Magnetic stirring iscarried out at 500 rpm for 24 hours at ambient temperature.

After one week, the samples are vacuum-filtered and rinsed with heptane.Each sample is analysed by PXRD for confirmation of the form obtained.After filtration, between 300 and 350 mg of anhydrous form D areobtained.

EXAMPLE 2

Approximately 3 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate aredissolved in a mixture of 50 mL ethanol+50 mL Polysorbate 80, pH 3.5.100 mL of water are added to the previous mixture and the whole ishomogenized. After storage for 48 hours at ambient temperature, crystalsof anhydrous form D appeared. The amount of crystallized productrecovered by filtration is approximately 2.45 g.

A comparative stability study was carried out between the acetonesolvate form A and the anhydrous form D. The comparison of the PXRDanalyses carried out on the A and D forms immediately after productionand after having maintained said forms at 40° C. for one month gives thefollowing results:

Form A: partial desolvation resulting in a mixture of the acetonesolvate form A and of the anhydrous form B being obtained.

Form D: no change detected after maintaining at 40° C. for one month.

What is claimed is:
 1. Crystalline forms of4-acetoxy-2α-benzoyloxy-5β,2α-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, withthe exception of the acetonate form.
 2. Forms according to claim 1,characterized in that they are anhydrous forms of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 3.Anhydrous form B of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 2, characterized by a PXRD diagram exhibitingcharacteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1,14.3, 15.4 and 15.9±0.2 degrees 2-theta.
 4. Anhydrous form C of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 2, characterized by a PXRD diagram exhibitingcharacteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9,12.3, 12.6 and 13.1±0.2 degrees 2-theta.
 5. Anhydrous form D of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 2, characterized by a PXRD diagram exhibitingcharacteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6,10.8, 11.1 and 12.3±0.2 degrees 2-theta.
 6. Anhydrous form E of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 2, characterized by a PXRD diagram exhibitingcharacteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7,13.2, 13.4 and 13.9±0.2 degrees 2-theta.
 7. Anhydrous form F of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-l-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 2, characterized by a PXRD diagram exhibitingcharacteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9,11.2, 12.1 and 12.3±0.2 degrees 2-theta.
 8. Forms according to claim 1,characterized in that they are ethanolic solvate or heterosolvate formsof4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 9.Ethanolate form B of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7α,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3 -tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 8, characterized by a PXRD diagram exhibitingcharacteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4,14.2, 14.7 and 15.1±0.2 degrees 2-theta.
 10. Ethanolate form D of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 8, characterized by a PXRD diagram exhibitingcharacteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5,11.1, 11.5 and 11.9±0.2 degrees 2-theta.
 11. Ethanolate form E of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 8, characterized by a PXRD diagram exhibitingcharacteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2,13.4, 13.9 and 14.2±0.2 degrees 2-theta.
 12. Ethanol/water heterosolvateform F of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionateaccording to claim 8, characterized by a PXRD diagram exhibitingcharacteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3,10.9, 11.2 and 12.2±0.2 degrees 2-theta.
 13. Forms according to claim 1,characterized in that they are hydrate forms of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13αyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 14.Monohydrate form C of4-acetoxy-2α-benzoyloxy-5β,2α-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 13, characterized by a PXRD diagram exhibitingcharacteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9,12.2, 12.6 and 13.3±0.2 degrees 2-theta.
 15. Dihydrate form C of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionateaccording to claim 13, characterized by a PXRD diagram exhibitingcharacteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7,12.3, 12.6 and 13.2±0.2 degrees 2-theta.
 16. Method for preparing theanhydrous form B according to claim 3, which consists in heating theacetone solvate form A between 100 and 110° C. under vacuum or nitrogensweeping, preferably for at least 9 hours, and then returning to ambienttemperature.
 17. Method for preparing the anhydrous form C according toclaim 4, by maturation of the acetone solvate form A, or of theanhydrous form B, in water, followed by drying up to approximately 50°C. and then maintaining at ambient temperature at a relative humidity ofless than 5%.
 18. Method for preparing the anhydrous form D according toclaim 5, by maturation, at ambient temperature, of the acetone solvateform A in ethanol and drying under nitrogen or under vacuum.
 19. Methodfor preparing the anhydrous form D according to claim 5, bycrystallization, at ambient temperature, of the acetone solvate form Afrom an oil, followed by rinsing with an alkane.
 20. Method forpreparing the anhydrous form D according to claim 5, by crystallizationof a solution of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate in amixture of Polysorbate 80, pH 3.5, ethanol and water (preferably, a25/25/50 mixture) for approximately 48 hours at ambient temperature. 21.Method for preparing the anhydrous form E according to claim 6, bymaturation of the acetone solvate form A in ethanol so as tointermediately form an ethanolic form which is subsequently desolvatedunder nitrogen sweeping or by heating at approximately 100° C. for 2hours and then returning to ambient temperature.
 22. Method forpreparing the anhydrous form F according to claim 7, by desolvating theethanol/water heterosolvate at 120° C. under a nitrogen atmosphere for24 hours and then maintaining at a relative humidity of 0% at ambienttemperature.